Evolutionary constraints in conserved nongenic sequences of mammals

Mammalian genomes contain many highly conserved nongenic sequences (CNGs) whose functional significance is poorly understood. Sets of CNGs have previously been identified by selecting the most conserved elements from a chromosome or genome, but in these highly selected samples, conservation may be unrelated to purifying selection. Furthermore, conservation of CNGs may be Caused by Mutation rate variation rather than selective constraints. To account for the effect of selective sampling, we have examined conservation of CNGs in taxa whose evolution is largely independent of the taxa from which the CNGs were initially identified, and we have controlled for mutation rate variation in the genome. We show that selective constraints in CNGs and their flanks are about one-half as strong in hominids as in murids, implying that hominids have accumulated many slightly deleterious Mutations in functionally important nongenic regions. This is likely to be a Consequence of the low effective Population size of hominids leading to a reduced effectiveness of selection. We estimate that there are one and two times as many conserved nucleotides in CNGs as in known protein-coding genes of hominids and murids, respectively. Polymorphism frequencies in CNGs indicate that Purifying selection operates in these sequences. During hominid evolution, we estimate that a total of about three deleterious Mutations in CNGs and protein-coding genes have been selectively eliminated per diploid genome each generation, implying that deleterious Mutations are eliminated from Populations non-independently and that sex is necessary for long-term Population persistence.